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MLK3 promotes atherosclerosis by regulating ferroptosis in macrophages
Hongkui Chen1,2, Jiabin Tu1,2, Ziqing Ruan1,2
1Department of Cardiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, China.
Background:
Atherosclerosis (AS) is the leading cause of cardiovascular death worldwide. Macrophage ferroptosis is implicated in AS progression. The precise mechanism by which mixed lineage kinase 3 (MAP3K11, MLK3) regulates macrophage ferroptosis in atherosclerosis is poorly understood.
Methods:
From the Gene Expression Omnibus (GEO) database, bulk and single-cell RNA-sequencing (scRNA-seq) datasets from vascular tissues were obtained. MLK3 was discovered to be a crucial ferroptosis-related gene (FRG) implicated in AS by means of differential analysis, weighted gene co-expression network analysis (WGCNA), and a ferroptosis gene set. Macrophages were shown to be the main cell type that expressed MLK3 when immune-infiltration profiling and single-cell RNA sequencing were combined. In vitro, macrophages were treated with Oxidized low-density lipoprotein (ox-LDL) or erastin, with or without MLK3 knockdown. Animal models assessed AS progression, ferroptosis, collagen deposition, and JNK/p53 activation. Immunofluorescence and clinical plasma MLK3 assays were performed.
Results:
MLK3 was predominantly expressed in plaque macrophages. Ox-LDL upregulated MLK3 and induced ferroptosis, while MLK3 knockdown attenuated ox-LDL-induced ferroptosis by suppressing JNK/p53 signaling, without affecting erastin-induced ferroptosis. Animal models showed increased MLK3 expression, ferroptosis, JNK/p53 activation, plaque area, and collagen deposition during AS progression. Immunofluorescence confirmed MLK3 co-localization with ferroptosis-associated proteins in plaque macrophages. Plasma MLK3 levels were consistently elevated in AS patients.
Conclusion:
MLK3 accelerates the development of atherosclerotic lesions by driving macrophage ferroptosis through JNK/p53 signaling.
Insights
Mixed lineage kinase 3 (MLK3) drives atherosclerosis by promoting macrophage ferroptosis via JNK/p53 signaling. Elevated plasma MLK3 levels indicate its role in cardiovascular disease progression.
Area of Science:
- Cardiovascular Biology
- Cellular Pathology
- Molecular Medicine
Background:
- Atherosclerosis (AS) is a leading global cause of cardiovascular death.
- Macrophage ferroptosis is a key process in AS development.
- The role of mixed lineage kinase 3 (MAP3K11, MLK3) in macrophage ferroptosis during AS remains unclear.
Purpose of the Study:
- To elucidate the mechanism by which MLK3 regulates macrophage ferroptosis in atherosclerosis.
- To investigate MLK3 as a potential therapeutic target for AS.
Main Methods:
- Analysis of bulk and single-cell RNA-sequencing data from vascular tissues.
- In vitro studies using macrophages treated with oxidized low-density lipoprotein (ox-LDL) or erastin.
- In vivo assessment in animal models of AS, including ferroptosis and JNK/p53 pathway activation.
- Clinical plasma MLK3 level assays in AS patients.
Main Results:
- MLK3 is highly expressed in atherosclerotic plaque macrophages and upregulated by ox-LDL.
- MLK3 knockdown inhibited ox-LDL-induced, but not erastin-induced, macrophage ferroptosis.
- MLK3 promotes JNK/p53 signaling, leading to increased ferroptosis, plaque area, and collagen deposition in AS models.
- Elevated plasma MLK3 levels were observed in patients with AS.
Conclusions:
- MLK3 accelerates atherosclerotic lesion development by inducing macrophage ferroptosis.
- The JNK/p53 signaling pathway is critical for MLK3-mediated ferroptosis in AS macrophages.
- Plasma MLK3 may serve as a biomarker for AS.
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